Abstract

OBJECTIVE Our objective was to examine the associations between concentrations of vitamin D and concentrations of insulin, glucose,
and HbA1c in a nationally representative sample of adolescents in the U.S.

RESEARCH DESIGN AND METHODS We used data for 1,941 adolescents, aged 12–17 years, who participated in the National Health and Nutrition Examination Survey
between 2001 and 2006.

RESULTS Adjusted concentrations of insulin were ~24% lower among male subjects with a concentration of vitamin D ≥75 nmol/L than
among male subjects with a concentration of vitamin D <50 nmol/L (P = 0.003). Concentrations of vitamin D were inversely associated with concentrations of glucose only among Mexican American
male subjects (P = 0.007). No significant associations between concentrations of vitamin D and HbA1c were detected.

CONCLUSIONS Our results support an inverse association between concentrations of vitamin D and insulin primarily in adolescent male subjects.

In recent years, the relationships between vitamin D and factors involved in glucose homeostasis have received a great deal
of attention. Few studies have been conducted using pediatric samples (1–3). Because the prevalence of deficient or insufficient vitamin D status is high among children and adolescents in the U.S.
and is possibly increasing (4,5), any deleterious effect of suboptimal vitamin D status on glucose homeostasis is of interest, especially in light of concerns
about increases in diabetes among youth in the U.S. (6). Most previous studies have used small, selected samples of adolescents. To provide additional insights into the associations
between circulating concentrations of vitamin D and concentrations of insulin and glucose, we examined data from a large,
representative sample of adolescents that included African Americans and Mexican Americans in the U.S.

RESEARCH DESIGN AND METHODS

We used data from the National Health and Nutrition Examination Survey (NHANES) 2001–2006 (7). The participants were recruited using a multistage, stratified sampling design, which is an efficient approach to obtaining
a sample representative of the civilian noninstitutionalized population. The participants were interviewed at home and were
invited to attend a mobile examination center, where they were asked to complete additional questionnaires, to undergo various
examinations, and to provide a blood sample. The study received approval from the NHANES Institutional Review Board, and participants
were asked to sign an informed consent form. Details about the survey can be found elsewhere (7).

Covariates included age, sex, race, or ethnicity (white, African American, Mexican American, other Hispanic, or mixed race),
leisure-time physical activity, BMI percentiles, supplement use during the past months (yes or no), concentrations of HDL
cholesterol and non-HDL cholesterol, and a 6-month sampling period. To estimate physical activity, we calculated an average
daily metabolic equivalent task hours index. BMI percentiles were calculated from measured weight and height using the Centers
for Disease Control and Prevention’s growth charts.

We limited our analyses to participants aged 12–17 years who attended the morning examination and who had fasted at least
8 h. We excluded participants who had been diagnosed with diabetes. Adjusted mean concentrations of insulin (after log transformation),
glucose, and HbA1c were calculated using ANCOVA. The statistical significance of the tests for linear trend of means conducted by using general
linear contrasts was assessed with an adjusted Wald F statistic that adjusts for the denominator degrees of freedom. The statistical software SUDAAN was used for the analyses
to account for the multistage, stratified sampling design.

RESULTS

During the 6-year study period, 2,070 adolescents, aged 12–17 years, attended the morning examination of the mobile examination
center. Data for concentrations of glucose, insulin, and vitamin D were available for 2,028 subjects. After excluding records
with missing data for covariates, the final analytic sample comprised 1,941 participants, including 531 whites, 620 African
Americans, 632 Mexican Americans, and 158 participants of another race or ethnicity.

Adjusted concentrations of insulin were approximately 24% lower among male subjects with a concentration of vitamin D ≥75
nmol/L than among male subjects with a concentration of vitamin D <50 nmol/L (P = 0.003) (Table 1). Concentrations of vitamin D were inversely associated with concentrations of glucose among Mexican American male subjects
(P = 0.007). No significant associations between concentrations of vitamin D and HbA1c were detected.

CONCLUSIONS

After adjusting for covariates, we found significant inverse associations between concentrations of vitamin D and insulin
among adolescent male subjects but not female subjects. Several previous reports have noted inverse relationships between
concentrations of vitamin D and surrogate measures of insulin resistance in samples of obese adolescents (1,2) and in a population-based sample of children and adolescents (3). Studies in animals and humans suggest that vitamin D status affects insulin secretion (10), vitamin D receptor expression (11), and tyrosine phosphorylation of insulin receptor substrate 1 (12).

The large, nationally representative sample of adolescents represents an important strength of our study. Several limitations
deserve to be acknowledged. The cross-sectional study design precludes establishing causality. The possible effect of the
use of different methods to measure concentrations of insulin, glucose, and HbA1c during the various survey cycles on our results is unclear. Concern has been expressed about possible assay variability for
the vitamin D assay in the NHANES (13). However, the apparent impact on vitamin D parameters for the period of 2000–2004 was small (14). We were unable to adjust for Tanner stage because this information was not collected.

Prospective studies and clinical trials are needed to clarify the relationships between concentrations of vitamin D and factors
involved in glucose homeostasis. Studies using gold-standard techniques to assess insulin resistance also would yield valuable
insights. The possibility that vitamin D may affect insulin resistance has potential implications for testing vitamin D concentrations
in children and adolescents; recommendations regarding the use of vitamin D supplements and sun exposure, especially in populations
at risk for insulin resistance; and fortification of foods. The prevalence of vitamin D deficiency and insufficiency is substantial
among adolescents in the U.S.; ~2% of adolescents had concentrations of vitamin D <27 nmol/L, 14% had concentrations <50 nmol/L,
and 33% had a concentration ≥75 nmol/L during 2001–2004 (4,5).

Acknowledgments

No potential conflicts of interest relevant to this article were reported.

E.S.F. researched data and wrote the manuscript. G.Z. researched data, contributed to the discussion, and reviewed and edited
the manuscript. J.T. contributed to the discussion and reviewed and edited the manuscript. C.L. contributed to the discussion
and reviewed and edited the manuscript.